Abstract
While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding). In contrast, inhibition of the nucleus accumbens (NAc), through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive.
Highlights
A fundamental barrier in treating obesity is the challenge associated with isolating individual feeding drives
Obesity can stem from excessive or binge-like consumption of food generated by different homeostatic and hedonic-related drives, each of which may involve distinct circuitry in the brain
This study extends earlier findings revealing that pituitary adenylate cyclase activating polypeptide (PACAP) administration into the hypothalamic ventromedial nuclei (VMN) markedly suppressed feeding behavior (Resch et al, 2011, 2013) by determining the capacity of this novel anorexigenic peptide to regulate distinct forms of eating stemming from homeostatic and hedonic feeding drives
Summary
A fundamental barrier in treating obesity is the challenge associated with isolating individual feeding drives. Understanding these could lead to the identification and development of potential new treatments based on the mechanisms underlying each unique form of caloric intake. The degree to which potential anorexigenic substances can suppress distinct feeding drives has been difficult to determine because feeding in many preclinical models likely involves multiple feeding drives. This is problematic with paradigms comparing the consumption of standard chow and highly-palatable food in combination with food deprivation. Homeostatic and hedonic drives are more clearly separated, which enabled us to examine the cellular and molecular components of each feeding drive
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
